CAREER: Innovative Strategies for the Synthesis of Unexplored Complex Bisindole Heterodimeric Alkaloids

About This Grant

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Filippo Romiti at the University of Texas at Dallas is studying the development of new chemical methods and synthesis strategies for the preparation of biologically active heterodimeric natural products. Pivotal to this work is the investigation of powerful and selective transformations that allow direct merger of monomeric natural products for the efficient generation of a wide array of complex heterodimeric bioactive natural products and new unnatural analogs. The targets identified for this program challenge the state-of-the-art in complex molecule synthesis and serve as springboards to design, discover, test, and improve novel chemical processes that can find applications in the preparation of pharmaceuticals, agrochemicals, and materials ultimately benefitting society. Undergraduates, graduate students and post-doctoral researchers rigorously trained through this research in the theory, methods, and strategies of synthesizing complex organic molecules will become future scientists in the chemical, pharmaceutical, biotechnological, and materials fields. Furthermore, this grant will allow to enhance hands-on research experiences for local community college transfer students and high school students. In partnership with Ottem Labs, a non-profit organization, the Romiti group will establish an outreach program for local high school students in order to ignite their interest in chemistry, the art of organic synthesis and science in general. Complex dimeric bisindole alkaloids display superior bioactivity respect to their monomeric constituents; however, their total syntheses are rare. This award will support the synthesis of several natural heterodimeric bisindole alkaloids featuring the development of new chemical transformations. The first project involves the investigation of a novel catalytic chemoselective amide reduction/Friedel-Crafts process as a powerful and efficient method to directly couple monomeric alkaloid units to generate complex heterodimeric alkaloids. The succinct synthesis of kopsoffine and pleiomutine showcases the utility of the method. The second project entails the development of novel approaches for the synthesis of bisleuconothines and angustifonines, two families of complex heterodimeric bisindole alkaloids with promising anti-cancer activity that have never been synthesized to date. The third project tackles the first total synthesis of criophylline through the development of a novel amine to lactam electrochemical oxidation. These studies are expected to advance the state-of-the-art in complex molecule synthesis and enrich the toolbox available to organic chemists. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.